Clinical Characteristics of Brazilian Patients with Paroxysmal Nocturnal Hemoglobinuria and Changing Prognosis with Eculizumab

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic cells due to acquired mutations in the phosphatidylinositol glycan class A (PIG-A) gene, which is required for glycosylphosphatidylinositol (GPI) anchor biosynthesis. This leads to partial or complete absence of all GPI-linked proteins, who are complement regulatory proteins, resulting in an increased sensitivity of the red blood cells to the action of complement. PNH is characterized by signs and symptoms related to intravascular hemolysis, hypercoagulability state, and varying degrees of medullary insufficiency. The anti-complement therapy radically changed the PNH patients outcomes. However, there are little data on the clinical characteristics of PNH in Latin American countries.

Methods: We performed a retrospective analysis of 109 patients with PNH clone followed from January 1987 until July 2019 in two Brazilian centers: Universidade Federal de Sao Paulo and Hospital Sirio Libanes (Sao Paulo-Brazil). Most patients (88%) were evaluated while the others had lost follow up or died and data was obtained from their medical reports. Patients were separated into 3 groups: classical PNH (n=44) PNH associated with other bone marrow disorder(n=12), and subclinical PNH, defined as PNH clone (at least 0.01% of cells with PNH clone) associated with another bone marrow disorder (n=53, aplastic anemia in 95% of cases). Median follow up was 60 months (range: 3-394).

Results: Median age at diagnosis was 41 years (range: 18-81), and 51% were male. Among the 56 patients with hemolytic PNH, 86% had fatigue, 66% hemoglobinuria, 45% abdominal pain and 16% dysphagia. Venous thromboembolism was observed in 14 cases (25%), with abdominal thrombosis in 7 cases (50%). Seven patients (13%) had arterial thrombosis (stroke or transient ischemic attack). Only 5 patients (10%) in the hemolytic group had acute renal failure and needed dialysis therapy due to a hemolytic crisis, but progressed to recovery of renal function after the event. No patient in this series had moderate or severe chronic kidney disease. Most hemolytic patients (73%) were treated with eculizumab, with a median time from diagnosis to the start of eculizumab of 25 months (range: 2-275). All eculizumab-treated patients had significant reduction in intravascular hemolysis with lactate dehydrogenase (LDH) normalization. Most had significant improvement in anemia, with increase in the median hemoglobin from 9.1 g/dL before treatment to 11.7 g/dL after eculizumab. The vast majority (94%) became transfusion-independent. Overall survival (OS) at 5 years was 100% at 5 years for classical PNH (n=44), 89% for subclinical PNH (n=53) and 71% for PNH associated with another bone marrow disease (n=12).

Conclusion: The clinical data and the distribution of the three subtypes of PNH in this study in this large series of Brazilian PNH patients were similar to other published series, except for a lower frequency of venous or arterial thrombosis in hemolytic patients before eculizumab treatment and a lower frequency of chronic kidney disease in our series. We also confirmed in our series the efficacy of eculizumab in controlling hemolysis and PNH-related complications and death risk.